key: cord-1013524-4zovn6gj authors: Behrouzi, Bahar; Araujo Campoverde, Maria Viviana; Liang, Kyle; Talbot, H. Keipp; Bogoch, Isaac I.; McGeer, Allison; Fröbert, Ole; Loeb, Mark; Vardeny, Orly; Solomon, Scott D.; Udell, Jacob A. title: Influenza Vaccination to Reduce Cardiovascular Morbidity and Mortality in Patients With COVID-19: JACC State-of-the-Art Review date: 2020-10-13 journal: J Am Coll Cardiol DOI: 10.1016/j.jacc.2020.08.028 sha: 330d1872f991888b42b3a21c4c117a30756b0b4a doc_id: 1013524 cord_uid: 4zovn6gj Viral respiratory infections are risk factors for cardiovascular disease (CVD). Underlying CVD is also associated with an increased risk of complications following viral respiratory infections, including increased morbidity, mortality, and health care utilization. Globally, these phenomena are observed with seasonal influenza and with the current coronavirus disease 2019 (COVID-19) pandemic. Persons with CVD represent an important target population for respiratory virus vaccines, with capacity developed within 3 large ongoing influenza vaccine cardiovascular outcomes trials to determine the potential cardioprotective effects of influenza vaccines. In the context of COVID-19, these international trial networks may be uniquely positioned to redeploy infrastructure to study therapies for primary and secondary prevention of COVID-19. Here, we describe mechanistic links between influenza and COVID-19 infection and the risk of acute cardiovascular events, summarize the data to date on the potential cardioprotective effects of influenza vaccines, and describe the ongoing influenza vaccine cardiovascular outcomes trials, highlighting important lessons learned that are applicable to COVID-19. One of the earliest reports of an association between respiratory infection and higher cardiovascular mortality was during the 1918 influenza pandemic (5) . Seasonal influenza epidemics have subsequently been associated with population-level increases in cardiovascular hospitalization and mortality (6) (7) (8) . In a typical year, influenza infections are associated with w225,000 hospitalizations, 36,000 cardiopulmonary deaths, and 51,000 deaths in the United States (6, 9) . The prevalence of influenza-related deaths has significantly risen in the last 2 decades, although it remains unclear whether this is due to changes in the demographics of the U.S. Viral respiratory infections, such as seasonal influenza and COVID-19, are associated with elevated risks of cardiovascular events. Several international CVOTs are investigating whether seasonal influenza vaccine reduces the risk of cardiovascular events among patients with HF or coronary artery disease. Existing trial networks may provide an opportunity to assess primary and secondary prevention strategies for patients with CVD at risk of complications from COVID-19. population, altered virulence of circulating strains of influenza, limitations in vaccination (effectiveness or uptake), or increased sensitivity of influenza virus testing (9) . For instance, the risk of cardiovascular complications from respiratory virus infections, including influenza, has become better recognized and characterized with improved methods of detection of subclinical and overt acute myocardial infarction (MI) and heart failure (HF) events associated with influenza-like illness among patients with or at risk of CVD (10) . Influenza Vaccines to Prevent Cardiovascular Events-Insights for COVID -19 arrhythmia (13) . Furthermore, influenza infection also predisposes patients to develop opportunistic infections like bacterial pneumonia, which in itself is associated with increased cardiovascular risk through a variety of effects on the cardiopulmonary system, from the vascular endothelium and peripheral vessels, to cardiac autonomic function and renal function (18, 19) . More directly, the influenza virus may precipitate acute cardiovascular events by stimulating a potent acute inflammatory response-a known trigger of acute plaque rupture and global myocardial depression (20) (21) (22) . Influenza virus can also directly infect tissue in the heart, lungs, and blood vessels, as seen in murine models and human atherosclerotic plaques (10, 23) . Accumulating data suggest that influenza infection and COVID-19 share a similar initial clinical presentation once symptoms develop, namely, fever, cough, and shortness of breath (24) . However, although the virus' true basic reproduction number (R0) is still under investigation, COVID-19 appears to be more transmissible (25) . This may be due to significant viral shedding prior to symptoms or because many infected persons may be subclinical or have a mild course of illness, thus facilitating transmission in community settings. Most patients develop no more than a self-limiting mild-to-moderate influenza-like illness. However, a subgroup of patients develop substantial cardiac and pulmonary morbidity and mortality, typically observed within 2 to 4 weeks following symptom development of COVID-19, similar to the trajectory described following the onset of acute respiratory infections and influenza virus (26) . Unlike influenza, COVID-19 is associated with a w10-fold higher hospitalization rate and a w5 to 10 times higher mortality rate (24, 27, 28 Beyond standard pathways described in the previous text, in which influenza and other acute respiratory infections can destabilize CVD patients, the specific mechanisms by which SARS-CoV-2 leads to acute myocardial injury are still emerging. The potential role of angiotensin-converting enzyme 2 (ACE2) receptor has recently been suggested as a possible link, perhaps even allowing for direct viral infection of the myocardium and vascular endothelium (31, 32, 37) . SARS-CoV-2 infection is triggered by binding of the spike protein of the virus to the ACE2 receptor, which is a highly expressed membrane-bound aminopeptidase in the heart and lungs. The ACE2 receptor has a vital role in the cardiovascular and immune systems, heart function, and the development of hypertension and diabetes mellitus (38) . Perhaps because the ACE2 receptor is also found in alveolar epithelial and endothelial cells, this may be a potential mechanism for development of thrombosis, including large vessel clots, deep vein thrombosis/pulmonary embolism, and disseminated microvascular thrombosis in the heart, liver, and kidneys among patients with COVID-19 (39) (40) (41) (42) (43) (44) . However, other immune activation pathobiology may be at play that is unique to COVID-19, such as the development of antiphospholipid antibodies among patients presenting with a hypercoagulable state and disseminated thrombosis (40) . Proinflammatory and prothrombotic effects that increase the risks of acute MI and heart failure. Patients with known CVD who get infected with influenza could also present with fever, tachycardia, potential volume overload, and arrhythmia. Proinflammatory and prothrombotic effects leading to acute MI or myocardial injury and heart failure, disseminated thrombosis, hypotension, arrhythmia, sudden cardiac death, and pediatric inflammatory multisystem syndrome. SARS-CoV-2 has also shown a similar profile to SARS-CoV for susceptible cell lines, which unfortunately suggests that embryonated eggs will not support SARS-CoV-2 replication as a culture system (62) . Also, although not seen yet, it is unclear how stable the SARS-CoV-2 genome is with regard to antigenic drift, as RNA viruses like influenza tend to mutate. The current lack of immune pressure for SARS-CoV-2 works in favor of its genomic stability; therefore, the hope of developing a vaccine that could offer nearterm protection is high (63) . There is also ongoing research to verify that immunity is established and can be prolonged following Several mechanisms may be at play to explain these findings. In addition to preventing infection and thus avoiding disruptions in homeostasis, the vaccine itself may interact with immune and inflammatory systems to promote plaque stabilization (106) . Vaccine-induced antibodies may also interact with the bradykinin 2 receptor, leading to increased nitric oxide production (107) . Behrouzi et al. Table 4) . With the ever-looming threat of future global respiratory viral outbreaks and their potential for downstream cardiovascular consequences, it is increasingly recognized that: 1) it is impossible to predict the next pandemic and its agent of cause (123, 124) ; and 2) our existing vaccine technologies and mass production infrastructures are not built to address pandemics in a timely manner to minimize human cost (125, 126) . It is also known that although the seasonal influenza vaccine is better than nothing, it is not nearly as effective as it can be, having ranged from 10% to 60% in estimated effectiveness in recent years (75) . In 2018 to 2019, the adjusted vaccine effectiveness for all influenza vaccines across all age groups was only 29%, which has only served to fuel vaccine hesitancy among the general public (127) . Hence, there is a need for a collaborative shift in focus toward developing and evaluating stronger formulations of the influenza vaccine, towards the goal of increased effectiveness and uptake, and perhaps ultimately, a universal influenza vaccine (128, 129) . Notwithstanding the research recommendations for influenza and COVID-19 provided throughout this review (summarized in As per NACI's recommendations (145) As per NACI's recommendations (145) *Information obtained from public statements on the corresponding institutions websites. †Information obtained from publicly available and approved guidelines. CVD ¼ cardiovascular disease, HF ¼ heart failure. Generating high-quality evidence on hard clinical outcomes that are important in these patient populations Ensuring evidence is externally valid and generalizable to global, diverse patient populations Evaluating a low-cost and ubiquitous intervention for a high morbidity and mortality disease phenotype Identifying the best influenza vaccine type for this high-risk patient population Arming cardiologists and CV specialists with evidence and patient education tools to properly combat vaccine hesitancy beyond the primary care setting Observational studies looking at short-term cardiovascular outcomes of COVID-19 in real-world, high-risk patients, e.g., INVESTED-COVID-19 Identifying clinical, social, and genetic determinants of incidence and severity of COVID-19-like illness in high-risk CVD patients Assessing the relationship between humoral response to influenza vaccination and susceptibility to COVID-19-like illness and its severity in high-risk CVD patients Delineate and substantiate correlates of immunity for both viruses and promising new vaccines Establishing the strength and longevity of the adaptive immune response following the use of promising universal vaccine candidates for influenza Outlining the relationship between humoral and cell-mediated immunity following natural infection, as well as following the use of promising vaccine candidates for COVID-19 Establishing the strength and longevity of the adaptive immune response following the use of promising vaccine candidates for COVID-19 Future research efforts Ongoing influenza CVOTs being redeployed to study COVID-19 vaccines in high-risk CVD patient populations, e.g., INVESTED, IVVE, and IAMI Leverage already existing global clusters of trialists and participants who meet the inclusion criteria for RCTs focused on high-risk CVD populations, who are also at high-risk for COVID-19 and downstream complications Potential vaccine candidates are first tested in healthy volunteers only, whereas potential treatment agents are immediately tested in current or high-risk patients; thus, it is important to also evaluate vaccine outcomes in high-risk populations Same as noted above for the impacts of ongoing influenza vaccine CVOTs, contextualized to COVID-19 vaccines Observational studies looking at short-and long-term cardiovascular outcomes of COVID-19 in the general and high-risk populations, e.g., those with pre-existing CVD Generate necessary evidence to fortify prevention, treatment, and supportive planning for patients facing vast uncertainties following a novel disease Generate necessary evidence on coinfections that may complicate disease and/or treatment course, e.g., influenza coinfection Generate necessary evidence on potential vaccination strategies and drug-drug interactions, e.g., between antithrombotic agents and COVID-19 treatments Preclinical evaluation of the mechanisms underlying the potential cardioprotective effects of different influenza and/or COVID-19 vaccine strategies Gain more information on the pathophysiology and molecular mechanisms underlying various CVD phenotypes Generate necessary evidence for further establishing a causal association Produce knowledge that can point to other potential prevention and/or treatment candidates for these infections in high-risk patients Safety and efficacy/effectiveness clinical trials for newly developed universal influenza vaccines in high-risk patient populations, e.g., those with pre-existing CVD Improve the cost-effectiveness of available vaccines for high-risk populations that have proven to show a poor response to currently licensed vaccines, e.g., high-risk CVD patients Same as noted above for the impacts of ongoing influenza vaccine CVOTs Knowledge translation and implementation of evidence via unified and interdisciplinary global policy and decision-making approaches Use lessons learned from informing global influenza vaccination guidelines and policies with the latest evidence to create guidance for COVID-19 vaccination Use lessons learned from global influenza vaccination guidelines and policies to catalyze implementation of corresponding guidance for COVID-19 vaccination Leverage momentum and investments made into combatting COVID-19 globally to also efficiently tackle other common viral respiratory epidemics and pandemics with high morbidity and mortality, especially in ubiquitous high-risk CVD patients CVOT ¼ cardiovascular outcome trial; RCT ¼ randomized controlled trial; other abbreviations as in Table 1 . 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